Cell-based immunotherapy is a therapy with curative potential for the treatment of cancer. T cells and other immune cells may be modified to target tumor antigens through the introduction of genetic material coding for artificial or synthetic receptors for antigen, termed Chimeric Antigen Receptors (CARs), specific to selected antigens. Targeted T cell therapy using CARs has shown recent clinical success in treating hematologic malignancies.
Multiple Myeloma, the second most common hematological malignancy, remains incurable despite recent advances in treatment protocols incorporating the immunomodulatory drugs (IMiDs) lenalidomide, and pomalidomide as well as the proteosomal inhibitors bortezomib and carfilzomib. A number of immunotherapeutic strategies are therefore being actively investigated in myeloma with the aim of improving disease-free survival. The evidence that myeloma is amenable to immunotherapy comes from the clinical experience of treating myeloma patients with allogeneic hematopoietic stem cell transplantation where a graft versus myeloma effect has been demonstrated in high risk patients (Krishnan, et al. Autologous haemopoietic stem-cell transplantation followed by allogeneic or autologous haemopoietic stem-cell transplantation in patients with multiple myeloma (BMT CTN 0102): a phase 3 biological assignment trial. Lancet Oncol. 12:1195-1203 (2011)) and from the use of donor lymphocyte infusions where response rates of up to 30-40% have been seen (Lokhorst, et al. Donor lymphocyte infusions for relapsed multiple myeloma after allogeneic stem-cell transplantation: predictive factors for response and long-term outcome. J. Clin. Oncol. 18:3031-3037 (2000); Salama, et al. Donor leukocyte infusions for multiple myeloma. Bone Marrow Transplant. 26:1179-1184 (2000)). Further supporting evidence comes from the successful therapeutic use of the IMiDs and from the promising results of clinical trials using monoclonal antibodies directed against the myeloma associated tumor antigens CS-1, CD38, CD56 and CD138 (Kaufman, et al. Elotuzumab in Combination With Lenalidomide and Low-Dose Dexamethasone in Relapsed or Refractory Multiple Myeloma. J. Clin. Oncol. 30:1953-1959 (2012)).
The neural cell adhesion molecule CD56 is one of the most frequently expressed antigens in myeloma and therefore a potential target for CAR immunotherapy. CD56 plays an important role in tumorigenesis by mediating cell-cell adhesion, thereby facilitating the interaction of myeloma cells with bone marrow stromal cells, as well as by promoting tumor cell migration, invasion and proliferation and inhibiting apoptosis (Gattenloehner, et al. Novel RUNX1 isoforms determine the fate of acute myeloid leukemia cells by controlling CD56 expression. Blood. 110:2027-2033 (2007)). CD56 is expressed normally on natural killer cells, a subset of T lymphocytes, neuroendocrine tissue and in the brain where its expression peaks during embryogenesis but remains expressed at low levels even in the adult brain. Importantly, it is uniformly expressed at a significantly higher density in over 70% of patients with myeloma (Tassone, et al. In vitro and in vivo activity of the maytansinoid immunoconjugate huN901-N2′-deacetyl-N2′-(3-mercapto-1-oxopropyl)-maytansine against CD56+ multiple myeloma cells. Cancer Res. 64:4629-4636 (2004)).
There has been emerging interest in cellular immunotherapy using T cells expressing either T cell receptors (TCRs) or CARs targeted against myeloma associated antigens following the successful use of CD19 targeted CARs in patients with chronic lymphocytic leukemia and acute lymphoblastic leukemia (Brentjens, R. J., et al. Eradication of systemic B-cell tumors by genetically targeted human T lymphocytes co-stimulated by CD80 and interleukin-15. Nature medicine 9, 279-286 (2003); Brentj ens, R. J., et al. CD19-Targeted T Cells Rapidly Induce Molecular Remissions in Adults with Chemotherapy-Refractory Acute Lymphoblastic Leukemia. Science translational medicine 5, 177ra138 (2013); Porter, et al. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N. Engl. J. Med. 365:725-733 (2011)). While there are various reasons to expect that adoptive T cell therapy may work well in multiple myeloma, expanding adoptive T cell therapy to myeloma also poses unique challenges. Unlike other B-cell malignancies, CD19 expression is seen in only 2% of myeloma patients (Bataille, R., et al. The phenotype of normal, reactive and malignant plasma cells. Identification of “many and multiple myelomas” and of new targets for myeloma therapy. Haematologica 91, 1234-1240 (2006)). Furthermore, unlike CD19, the common extracellular immunophenotypic markers in myeloma (CD138, CD38, and CD56) are all co-expressed on other essential cell types, and it is predicted that CARs to any of these targets would lead to unacceptable “off tumor, on target” toxicity (Brentj ens (2013)) which can be fatal even in targets where antibodies are well tolerated, as was the case with a HER2 targeted CAR (Morgan, R. A., et al. Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Molecular therapy: the journal of the American Society of Gene Therapy 18, 843-851 (2010)). Accordingly, there are needs for novel therapeutic strategies to design CARs targeting antigens that are highly expressed in multiple myeloma cells and limited expression in normal tissues for treating multiple myeloma, and for strategies capable of inducing potent tumor eradication with minimal toxicity and immunogenicity.